How to successfully protect antibodies at the EPO
A majority of the top 10 blockbuster drugs are antibodies. Antibody therapies are booming. This is the result of continuous research efforts that are still ongoing.
These massive research activities are first translated into massive patenting. The introduction of a section dedicated to antibody drafting in the Guidelines for Examination at the European Patent Office (EPO) in March 2021 is an illustration of the importance of antibody patenting.
Based on a few decisions of the Boards of Appeal of the EPO and on some explanations provided by the Guidelines for Examination at the EPO, this article provides some insights as to successful antibody claim drafting at the EPO.
Defining an antibody by functional features
It may be tempting to define an antibody by solely relying on its activity or its function. For example:
- an antibody that binds protein Y; or
- an antibody that binds protein Y and does not bind proteins X or Z.
If protein Y is novel, the antibody defined under point (1) is likely also novel.
If protein Y is not novel and several antibodies targeting this protein have been published in the art, would the antibody defined under point (2) still be novel? Most probably the antibodies of the art have only been characterised in relation to their activity/function against protein Y. It may be challenging for the applicant to assess whether all published antibodies targeting Y would not target proteins X or Z.
As explained in the Guidelines for Examination at the EPO (G-II, 220.127.116.11), defining an antibody exclusively by functional features is at the risk of the applicant who has the burden of proof of novelty:
If an antibody is claimed exclusively by functional features and the prior art discloses in an enabling manner an antibody directed to the same antigen using an immunisation and screening protocol that arrives at antibodies having the claimed properties, it has to be assumed that the prior-art antibody inherently displays the same functional properties as the claimed antibody, which lacks novelty (cf. G-VI, 6). On the other hand, if the antibody is defined by unusual parameters, care has to be taken that these do not disguise a lack of novelty (F-IV, 4.11.1). In both these cases the burden of proof of novelty resides with the applicant.
Defining an antibody by exclusively relying on functional features potentially provides a broad scope of protection. The applicant should be prepared to be challenged on novelty and should be able to demonstrate the novelty of its antibody. Complementing and possible alternative ways of defining the antibody should be present in the application.
In decision T 0032/17 of the Board of Appeal of the EPO, it was held that a ‘product by process’ feature, referring to a group of specific deposit numbers, did not confer any additional technical feature to the antibody claimed.
The claim in question reads as follows:
A monoclonal antibody which is able to recognise 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 and which is produced from a hybridoma selected from the group consisting of the hybridomas deposited in the BCCM/LMBP under deposit numbers LMBP 7011CB, LMBP 7012CB, LMBP 7013CB, LMBP 7204CB and LMBP 7205CB.
The Board held that:
- the deposit number merely discloses the identity of the institute at which the hybridomas had been deposited and does not provide any structural information as to the antibody claimed;
- the use of the ‘product by process’ feature was only allowed in a claim provided it was impossible to define the product another way and provided the claimed product would meet the patentability requirements. The skilled person knows that antibodies could be defined using their amino acid sequences and this was not the case here; and
- the burden of proof of novelty resides on the patentee to demonstrate that the antibodies defined using this ‘product by process’ feature, referring to a deposit number, would be novel over antibodies of the prior art.
As a result, the Board only considered the functional feature defining the antibody, and this claim was not novel over antibodies of the prior art.
This recent and first decision of this kind is potentially alarming for applicants. In the past, such reference to a deposit was quite common for defining antibodies. If this deposit feature is present in a claim, we advise to have alternative strategies in place, such as disclosure of the amino acid sequence of the antibody in the application as filed.
Defining an antibody by structural and functional features
A basic mix of structural and functional features
Claiming an antibody, relying on structural features (full sequence or complementarity-determining region (CDR) sequences) and indicating a basic activity/function (binding a given enzyme) should meet the industrial applicability (Article 57 EPC) requirements of the EPO. Such antibody may also be novel (Article 54 EPC).
When will such antibody be considered inventive? For example:
- an antibody binding enzyme Y and this antibody being represented by amino acid sequence SEQ ID NO: x; or
- an inhibitory antibody against enzyme Y and this antibody being represented by amino acid sequence SEQ ID NO: x.
The antibody defined in point (1) may not be considered inventive if other antibodies binding enzyme Y were already known in the art. The same would hold for the antibody defined under point (2) if antibodies inhibiting enzyme Y were already known in the prior art.
Finding a new antibody targeting a known target is not sufficient for establishing the presence of an inventive step. In other words, ‘structural non-obviousness’ does not equal the presence of an inventive step.
This antibody, being novel by virtue of its sequence, needs to exhibit a specific attractive functional feature that was not yet known for this type of antibody in order to be considered inventive by the EPO. These surprising functional features may be as defined in the Guidelines for Examination (Guidelines G-II, 5.6.2):
The subject-matter of a claim defining a novel, further antibody binding to a known antigen does not involve an inventive step unless a surprising technical effect is shown by the application. Examples of surprising technical effects when compared to known and enabled antibodies are, for example, an improved affinity, an improved therapeutic activity, a reduced toxicity or immunogenicity, an unexpected species cross-reactivity or a new type of antibody format with proven binding activity.
It therefore means that relying on the structure and the basic function/activity of an antibody may not be sufficient to get a patent at the EPO.
A more elaborate mix of structural and functional features
In decision T 0941/16 of the Board of Appeal of the EPO, the applicant claimed a monoclonal antibody that was defined by several structural (features (d) and (e)) and functional ((a), (b) and (c)) features.
Claim 1 reads as follows:
1. An isolated monoclonal antibody or an antigen binding portion thereof which a) binds to prostate specific membrane antigen
in its native form occurring on the surface of
b) can be internalised by a tumour cell,
c) binds strongly to LNCAP cells but not or
only minimally to cells which lack expression of
prostate specific membrane antigen and
d) is linked to a label or a cytotoxic agent,
characterised in that
e1) it comprises at least three of the CDR
sequences selected from the group consisting of the CDRs designated as CDR H1, H2, H3, L1,
L2 and L3 as shown in Fig. 21
e2) it comprises at least three of the CDR
sequences selected from the group consisting of
the CDRs designated as CDR H1, H2, H3, L1,
L2 and L3 as shown in Figure 20.
The Board held that:
- the application as filed only discloses a murine antibody with the six CDRs of figure 20 or 21. No humanised antibody fulfilling all functional features of claim 1 and having only three murine CDRs as identified in claim 1 would have been disclosed in the application as filed;
- the application as filed merely refers to some humanisation protocols in general; it does not comprise specific technical guidance for the skilled person to obtain the antibodies of claim 1.
Moreover, the application does not contain any examples of a human antibody falling under the scope of claim 1;
- post-published documents submitted by the applicant were considered not relevant or were considered not to provide any compelling evidence that defining an antibody by only three out of its six CDRs would be sufficient; and
- the evidence submitted by the applicant demonstrated that the specificity and affinity (ie, some of the functional features) of a human antibody would be determined by CDR H3 and L3 – both being not present in all the antibodies claimed, according to feature (e) of the claim.
Table 1. Summary of the impact of structural and functional features when assessing each of the EPO requirements
(optional with sequence identity)
|Novelty (Article 54)||Safest way to establish novelty||Could be used to establish novelty but risky|
|Inventive step (Article 56)||Could be used if a given structural domain confers an activity/function||Crucial to define the inventive concept. Data may be needed to demonstrate the technical effect conferred by this feature|
|Sufficiency of disclosure|
|Key to have a representative number of antibodies disclosed fulfilling both requirements (especially when a family of antibodies is claimed at a conceptual level)|
The Board concluded that the application was not sufficiently disclosed (Article 83 EPC).
This case illustrates that defining an antibody using structural and functional features is not always the winning recipe at the EPO.
The presence of several functional features
(ie, features (a), (b) and (c) of the claim) were sufficient to define an antibody exhibiting surprising activity. This antibody should be considered inventive according to the Guidelines (G-II, 5.6.2).
However, one of the structural features (ie, feature (e) of the claim) needed to be more specifically defined to meet the requirements of sufficiency of disclosure. The issue with feature (e) may have been solved if the applicant had rendered mandatory the presence of the six CDRs.
Novelty of an antibody could be conferred by its structure (ie, sequence). However, such a new antibody is not inventive if other antibodies targeting the same target are already known in the art. The presence of an inventive step will only be acknowledged when this new antibody exhibits a specific property/function/activity that is attractive for solving the technical problem underlying the invention.
Moreover, when claiming a family of antibodies defined at the structural and functional levels, sufficient guidance should be present in the application: a representative number of these functional antibodies should be at least envisaged at the conceptual level, and ideally a representative number of antibodies should be disclosed in the application. If this is not the case, the applicant should be prepared to use alternative ways of defining its antibody, being more specific at the structural level while relying on some functional features for which experimental evidence is present in the application as filed.
There is no golden rule at the EPO. In most cases, antibodies should be defined using both structural and functional features. Table 1 provides a summary of the impact of structural and functional features when assessing each of the EPO requirements.
Structural features help to establish the novelty of the antibody. Such structurally defined antibodies are sufficiently disclosed. However, the scope of protection of these antibodies may not be considered broad enough by the applicant.
On the other hand, using only functional features to define an antibody provides a broad scope of protection, but this scope may be challenged by the EPO or third parties.
Depending on the prior art and on the amount of experimental data in the application, we advise that one design several alternative strategies in the application to define the antibody in the broadest way possible for the EPO and for each of the other envisaged jurisdictions.